Fluorinated heterocycles are an important class of compounds found in biologically active molecules and materials (a. Erian, A. W., J Heterocyclic Chem, 2001, 38, 793; b. Kirsch, P., Modern fluoroorganic chemistry: synthesis, reactivity, applications; Wiley-VCH; Weinheim; Great Britain, 2004; c. Bégué, J.-P.; Bonnet-Delpon, D., Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons: Hoboken, N.J., 2008). The selective introduction of fluorine into small molecules can lead to subtle or profound effects on the conformation, solubility and stability of a molecule compared to the non-fluorinated counterpart. The introduction of fluorine into a basic heterocycle can modulate the basicity and binding properties with only a small change in the steric environment. These effects are especially prevalent in 2-fluoropyridines because of the close proximity of fluorine and nitrogen. One example of the influence of fluorine in the 2-position of a pyridine is seen in the improved potency, cell activity, and selectivity of the 2-fluoropyridyl containing anti-cancer compound BMS-754807 compared to the non-fluorinated analogue (Wittman, M. D.; Carboni, J. M.; Yang, Z.; Lee, F. Y.; Antman, M.; Attar, R.; Balimane, P.; Chang, C. Y.; Chen, C.; Discenza, L.; Frennesson, D.; Gottardis, M. M.; Greer, A.; Hurlburt, W.; Johnson, W.; Langley, D. R.; Li, A. X.; Li, J. Q.; Liu, P. Y.; Mastalerz, H.; Mathur, A.; Menard, K.; Patel, K.; Sack, J.; Sang, X. P.; Saulnier, M.; Smith, D.; Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G. F.; Zimmermann, K.; Vyas, D. M., J. Med. Chem. 2009, 52, 7360). 2-Fluoropyridines enriched in 18F are valuable as radiotracers in PET imaging (a. Dolle, F.; Valette, H.; Bottlaender, M.; Hinnen, F.; Vaufrey, F.; Guenther, I.; Crouzel, C., J Labelled Compd Rad 1998, 41, 451; b. Dolci, L.; Dolle, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C., J Labelled Compd Rad 1999, 42, 975; c. Karramkam, M.; Hinnen, F.; Vaufrey, F.; Dolle, F., J Labelled Compd Rad 2003, 46, 979; d. Inkster, J. A. H.; Guerin, B.; Ruth, T. J.; Adam, M. J., J Labelled Compd Rad 2008, 51, 444).
Moreover, 2-fluoropyridines exhibit unique reactivity as synthetic intermediates compared to other halogenated pyridines. Thus, a convenient route to 2-fluoroazines allows the preparation of 2-amino, alkoxy, and alkyl azines, as well as pyridines containing halogens and additional functionality at the other positions of the ring for further manipulations.
The conditions typically used to form heteroaryl-fluorine bonds are harsh; thus the fluorine is usually introduced into the heteroarene ring at the beginning of a synthesis or as part of a building block. Improved methods for late-stage heteroaromatic fluorination would be important for diversification in medicinal chemistry. Moreover, methods for heteroaromatic fluorination with simple fluoride sources would be valuable for the preparation of 18F labeled compounds used in PET imaging. Yet, no general method has been reported for the fluorination of aryl halides.
Although 2-fluoroazines have favorable physical properties and are valuable synthetic intermediates, they are difficult to prepare when the azine contains other functional groups. The most practiced laboratory methods for the synthesis of 2-fluoropyridines are the Balz-Schiemann reaction of 2-aminopyridines and nucleophilic aromatic substitution of electron-deficient 2-chloro or 2-nitropryidines with an anhydrous fluoride source (Scheme 1). While these methods are useful for the synthesis of simple 2-fluoropyridines, the strongly acidic or basic reaction conditions and the need for pre-functionalized substrates limit their synthetic utility. The direct fluorination of pyridines and diazines with F2 is also known. However, the use of F2 gas is not practical in a typically laboratory setting because of the hazards associated with this gas, and the reactions with F2 occur in low yield, often give a mixture of products, and have only been demonstrated with very simple substrates.

Accordingly, a reaction that directly fluorinates a nitrogen-containing heteroarene precursor to form the corresponding fluorinated heteroarene at low to modest temperatures (e.g., <100° C.) would represent a significant advance in the art of heterorene fluorination and the provision of nitrogen-containing fluoroheteroarenes. Further, a reaction that leads to the mono-fluorination of a nitrogen-containing heteroarene precursor at a positions α- to the nitrogen would be of considerable utility, due to the strong influence of the introduced fluorine on the electronic properties of the nitrogen and the ability to replace this fluorine with common nucleophiles Moreover, such a reaction that did not degrade or react appreciably with substituents on the heteroarene nucleus would also be of great value. Surprisingly, the present invention provides such a reaction, compositions of use in carrying out this reaction and fluorinated nitrogen-containing heteroarene compounds prepared by the reaction.